TW200927740A - Process - Google Patents

Abstract

Compounds of formula I, V, VI and II, and processes for their preparation, wherein R1, R2 and R3 are the same or different and signify hydrogens, halogens, alkyl, alkyloxy, hydroxy, nitro, alkylcarbonylamino, alkylamino or dialkylamino group; and R4 is alkyl or aryl. There is also provided a process for preparing a compound of formula B from the compounds of formula V and I.

Description

200927740 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to an improved process and novel intermediate for the preparation of intermediates suitable for the synthesis of peripherally-selective inhibitors of dopamine-β-hydroxylase. [Prior Art] (R)-5-(2-Aminoethyl)-1-(6,8-difluoro '7 g of hydrazin-3-yl)-1,3-dihydro 11-mazole-2 -thione hydrochloride (compound of formula P below) is an effective, non-toxic, and peripherally selective inhibitor of ϋβΗ, which is useful in the treatment of certain cardiovascular conditions. The compound oxime together with its preparation method is disclosed in WO 2004/033447 〇

The method disclosed in W〇2004/033447 includes (R)-6,8-difluoroguanidine-3-ylamine hydrochloride ((R)-6,8-difluoroindol-3-ylamine The structure is as shown in the following compound Q), [4_(t-butyldimethylsilylalkyloxy)_3_sideoxybutyl]aminocarboxylic acid tert-butyl ester and potassium thiocyanate.

NH2

Q(R)-6,8-difluoroacridin-3-ylamine (Compound Q) is a key intermediate in the synthesis of compound 135964.doc 200927740. The stereochemistry at the carbon atom to which the amine is attached gives compound P a stereochemistry' so it is advantageous for compound Q to be as pure as possible. In other words, 'the R enantiomer of the compound should be predominant, with little or no S enantiomer. [Explanation] It has now been found to be advantageous to prepare an intermediate suitable for the synthesis of compound P. The intermediate is a compound of formula B.

Such advantageous methods include the compound of formula VII

Conversion to a compound of formula B wherein the rule 4 is an alkyl or aryl group and & is % or -NH2. One method involves the conversion of a carboxy azide (i.e., a compound of formula VII having a core of _n3) to a compound of formula B. The carboxy azide can be prepared from the corresponding carboxylic acid. The corresponding slow acid can be prepared from the corresponding nitrile. The corresponding nitrile precursor can be prepared from the corresponding phenolic compound. Another method involves the conversion of a brewing amine (i.e., a compound of formula VII of size 5 to y-2) to a compound of formula B. The guanamine can be prepared from the corresponding nitrile. The nitrile can be prepared from the corresponding aldehyde. The aldehyde precursor can be formed from the corresponding phenolic compound. Thus, in the broadest aspect, the invention provides a process for the preparation of a compound of formula B 135964.doc 200927740 which comprises converting a compound of formula VII to a compound of formula B r2 lx/ R«

VII r3 0 Β ❹ ❹ wherein Ri, R 2 and R 3 are the same or different and represent hydrogen, halogen, aryl, alkyloxy, hydroxy, nitro, alkylcarbonylamino, alkylamino or dialkylamine R4 is alkyl or aryl; and R5 is -N3 or -NH2, wherein: the term alkyl means straight or branched, containing from one to six carbon atoms, optionally aryl, alkoxy, or a hydrocarbon chain substituted with a hydrazine, an alkoxycarbonyl group or a hydroxycarbonyl group; the term aryl means a phenyl or a phenyl group substituted by an alkyloxy group, a aryl group or a nitro group, and the term _ 素 means gas, chlorine, desert Or moth. In an embodiment, Rs is -Ν3. Or R5 is ·Νη2. The conversion method suitably includes a rearrangement reaction. When R·5 is -Ν3, the recombination reaction may comprise a Curtius recombination reaction. When R5 is -NH2, the recombination reaction may comprise a Hoffman recombination reaction. [Embodiment] According to one aspect of the present invention, there is provided a method of preparing a compound of Formula B,

The method comprises the compound of formula I

Converted to a compound of formula B, where Ri, heart and! ^ is the same or different and represents 135964.doc -9- 200927740 hydrogen, halogen, alkyl, alkyloxy, hydroxy, nitro, alkylcarbonylamino, alkylamino or dialkylamine; 4 is an alkyl group or an aryl group, wherein: the term alkyl means a straight or branched hydrocarbon chain having one to six carbon atoms, optionally substituted by an aryl group, an alkoxy group, a halogen, an alkoxycarbonyl group or a hydroxycarbonyl group. By S, aryl refers to a phenyl or naphthyl group optionally substituted with an alkyloxy group, a dentate or a nitro group; and the term halogen means fluorine, gas, bromine or iodine.

In one embodiment, at least one of R1, R2, and K·3 is fluorine. In another embodiment, Compound I has the formula J A

In an embodiment, R4 is a Cl to C4 alkyl group. R4 is optionally a thiol group, an ethyl group or a tert-butyl group. R4 is preferably a methyl group. In another embodiment, R4 is benzyl. In an embodiment ❹ the method is as follows.

The conversion of I to form B can encompass the recombination reaction of decylamine to form a urethane acetonate such as Hoff. The recombination reaction can be carried out in the sub-acid salt and the alcohol of the formula R4〇H (wherein the rule 4 has the same meaning as given above:

light. R·4 is appropriately A I

base. . The popular acid salt is usually an alkali metal salt of a sub-acid, such as sodium hypochlorite. Ha·A A shows a hypohalite other than the long-acid acid salt, for example, 135964.doc 200927740 bromate, which can also be used in the recombination reaction. The conversion of j formation 6 suitably comprises a recombination reaction in the presence of sodium hypogasate and methanol. In one embodiment, the compound and the alcohol R4〇H may be at a ratio of about 1 (rc or less, preferably 5). (: stirring at the following temperature, followed by an aqueous solution of an alkali metal hypoalkite (usually sodium hypochlorite) The reaction is carried out at a rate to maintain the internal temperature below 1 Torr. The reaction can then be stirred at 5 ° C for a period of time, usually 3 Torr. Then by adding a base such as an alkali metal hydroxide, usually hydrating The solution (in a charged reaction at a rate to maintain the internal temperature below about 1 G ° C) to verify the reactants comprising the N-gas guanamine intermediate. The reaction temperature can then be maintained below 1 (rc) For a period of time, usually about 3 minutes, the temperature of the reactants is then adjusted to about 2 (TC to about 3 (in the range of rc, typically 2 rc. This temperature can then be maintained in the range of about 15 hours to about 30 hours, usually A period of from about 20 hours to about 25 hours, followed by adjustment of the reactants to a temperature below 10 ° C, typically about 5 ° C, followed by loading of an acid such as hydrochloric acid, and maintaining the temperature of the resulting suspension at about , lasting at least (one), time. Then you can pass #filter product and water Methanol (usually 1:1, KOi MeOH) is washed and dried in vacuo to give compound B as a white crystallite solid. For example, the product can be purified by recrystallization to form a conversion product of B. It can be present in a mixture of water and 2-propanol. Recrystallization is achieved. According to another aspect of the invention, there is provided a method of producing a compound of formula j as defined above. The method comprises converting a compound of formula π to a compound of formula 1, wherein R丨, R2 and I have the same as above Given the same meaning of 135964.doc 200927740.

In one embodiment, at least one of Ri, R2, and R3 is fluorine. In one embodiment, the compound of formula II has formula IIA

„A

The conversion of F π to form i may comprise hydrolysis in the presence of a mineral acid and an organic acid. The inorganic acid can be sulfuric acid. The organic acid can be acetic acid. The reaction medium can be a mixture of acetic acid and sulfuric acid. In one embodiment, the mineral acid is added to the compound π in the organic acid with stirring at a temperature of from about 15 ° C to about 25 t, typically about 20 ° C. The temperature of the reactants can then be increased to between about 8 Torr and about 11 Torr. Within the scope of 〇, it is usually about 1 〇〇. . The temperature is maintained for a period of time, typically about 45-90. (eg 60 minutes). The temperature of the reactants can then be lowered to about hunger to about 35 C', typically about 3 Torr. At a temperature and for a period of time (usually about 2 minutes) an aqueous alcohol (such as aqueous isopropanol (usually 2:1, water: ιρΑ) is charged to the reaction product. The temperature of the reactants can then be lowered below The temperature of the HTC (usually 5. 〇' and maintained at this temperature for at least 2 hours. The product can then be filtered and then treated with an aqueous alcohol solution (such as aqueous isopropanol (usually 2:1, water: ιρΑ), alcohol and test (such as An aqueous solution of a metal hydroxide, preferably a potassium hydroxide solution, and finally an aqueous alcohol solution (such as aqueous isopropanol (usually hydrazine, water: called a sulphur cake). The product can then be dried under vacuum in a thief. Compound I ° In one embodiment, the method is as follows. 135964.doc 200927740 Ο

R

NH2 F

IIA IA A compound of formula II as defined above may be obtained by formulating a compound of formula III R2

OH

III ❹ is prepared by conversion to a compound of formula II wherein Ri, and R3 have the same meanings as given above.

In one embodiment, at least one of R!, Ruler 2, and R3 is fluorine. In one embodiment, the compound of formula III has formula IIIA

The conversion of IIIA III to Form II includes a cyclization condensation reaction such as reacting a compound of formula III with acrylonitrile in the presence of 1,4-diazabiindole [2.2.2] octane (DABCO). The reaction mixture can be heated to a high temperature, such as 50. (: to a temperature in the range of 90 ° C, preferably in the range of 60 ° C to 80 ° C, more preferably about 70 ° C. The reaction can be carried out in pure acrylonitrile or using a solvent such as acetonitrile or DMF. Compounds can be obtained by formulating compounds of formula IV

Prepared by conversion to a hydrazine compound, wherein R1, Rz and & have the same meaning as 135964.doc 13-200927740 ijU I dragon above. In one embodiment, at least R丨, Rz and R3 One

', ', ° In one embodiment, the compound of formula I has formula IVA

Conversion of F IVA IV to Form III can include reacting a compound of Formula IV with a oximation agent. In one embodiment, the reaction is carried out in the presence of an acid. The formazonating agent can be hexamethylenetetramine and the acid can be trifluoroacetic acid. After the addition of the formazan, the temperature of the reaction mixture may be raised, for example, to a range of from 6 Torr to 100 ° C, preferably from 7 Torr to 9 CTC, preferably to about 80 ° C. The temperature. This temperature can be maintained for a period of time, for example, at least 60 minutes. The temperature of the reaction mixture can be further raised to from about 90 C to about 130. (In the range, preferably about 1 Torr (r to about 12 〇c> c, the temperature is more preferably raised to about 115. The temperature of 〇. The reactant can then be cooled. ' For example, cooling to about HTC to Approximately 45. (: Fan _, preferably from about 赃 to about t 35t. More preferably about 30. °. Water may be added to form a suspension. The suspension may be filtered and washed with water. The suspension can be used directly to form the compound of formula 11, i.e., without a separate separation step. In the examples, the invention provides a method of preparing a compound of the formula shown below.

135964.doc • 14- 200927740 More specifically, the method of the present invention may include the following steps:

0

A method of preparing a compound of formula B according to another aspect of the invention

The B 5 mysterious method comprises a compound of formula V

Conversion to a compound of formula B wherein Ri, scales 2 and 1 are the same or different and represent hydrogen, dentate, alkyl, alkyloxy, hydroxy, nitro, alkylcarbonylamino, alkylamino or dialkyl An amino group; and the quaternary 4 is an alkyl or aryl group, wherein: the term alkyl means straight or branched, containing from one to six carbon atoms, optionally aryl, alkoxy, dentate, alkoxy A hydrocarbon chain substituted with a carbonyl group or a hydroxycarbonyl group; the term aryl means a phenyl or naphthyl group optionally substituted with an alkyloxy group, a self- or a nitro group; and the term _ means means fluorine, gas, bromine or iodine. In one embodiment, at least Rl, chemistry, and heart are fluorine. In another embodiment, compound V has the formula 135964.doc •15· 200927740 Ο

Ν - In one embodiment, the heart is a ^ or a butyl group. R4fe is preferably A & = R4, depending on the case, thiol and ethyl. In another embodiment, r4 is benzyl hydrazine. In one embodiment, the method is as follows.

^ F Vi?vV^/NHC02Me

The conversion method in which W V forms B may include the same meaning as given above in the case of the machine h), in the case of Ri, as in the case, the thermal decomposition includes the Kurtis weight: the inverse π solution. In a compound of Example V, the compound is dissolved in an organic solvent, and the compound is heated to an organic solvent. Suitable solvents include any substantially inert agent such as dioxane, toluene or acetic acid. Ethyl acetate. Alternatively, the formula (4) can be used as a solvent and a reagent. The compound is dissolved in the organic solvent and can be used at a south temperature, for example, at 3 5 0 Ρ Φ δ η 0〇* 』 at 35 (: to 8 〇) (: 'It is preferably at a temperature in the range of 70 Torr, preferably at a temperature of about 6 Torr. After the reaction is completed, the reaction mixture can be cooled, concentrated as appropriate and a second organic solvent is added to make Formula B Crystallization of the compound. The second organic solvent can be any saturated hydrocarbon solvent, such as petroleum ether, hexane or heptane. If the first organic solvent is miscible with water, then water can be added to crystallize the compound of formula B. It can be cooled 135,964. Doc •16- 200927740 to 3 〇C or less, preferably a temperature below 15 ° C. It should be understood that the oxygen atom T of the 5 c cj ru is replaced by a CH 2 group or s atom, so that The ring structure becomes a naphthyl ring or a sulfur π-complete ring, respectively, and V forms B. Above for the conversion process to follow. After the same manner as the base for the ring. According to another aspect of the present invention, there is provided a process for preparing a compound of formula V as defined above, the composition. The method comprises the compound of formula VI

ΟΗ

VI is converted to a compound of formula V wherein Ri, 1 and 3 have the same meaning as given above.

In one embodiment, at least one of R1, R2, and R3 is fluorine. In one embodiment, the compound of formula VI has formula VIA

The conversion of VIA 〇VI to form V may include the use of a sulfhydryl azide former typically in the presence of a water miscible solvent and optionally a base, examples of which are those skilled in the art. Well known. Water can also be present. The mercapto azide forming agent may be a diphenylphosphonium-based lamination in the presence of a base. The water-miscible solvent may be acetone, acetonitrile, DMF, THF, dioxane or hydrazine, 2-dimethoxy ethane. The base is preferably a weak base and may be triethylamine, tripropylamine or tributylamine. For example, by adding cold water to the reaction mixture, the compound of formula V can be made from its 135964.doc •17·200927740. The suspension can then be cooled, filtered and adapted to take the wet cake. The solution of the compound in the extraction of the organic solvent can be directly used for conversion to hydrazine as described, i.e., without a separate separation step. /Understanding that the oxygen atom in the ring can be called a group or s atom substitution, so that the structure of the seedlings becomes a naphthyl ring or a "base ring", and the formation of VI can be carried out in the same manner as described above with respect to the wire ring. . Conversion Ο According to another aspect of the invention, there is provided a process for the preparation of a compound of formula VI as defined above. The method comprises converting a compound of formula II to a compound of formula V wherein +R|, m3 have the same meaning. In one embodiment, at least one of R1, m3 is 1 in the embodiment, the compound of formula II has the formula

The formation of ΙΙΑ 11 to form a conversion of vl can include hydrolyzing a nitrile having the formula η. Hydrolysis can involve treatment of a compound of formula II with a test such as sodium hydroxide, hydroxide or hydrazine in the presence of hydrazine followed by treatment with an acid such as hydrochloric acid, sulfuric acid or phosphoric acid. Should understand. The oxygen atom in the ring can be replaced by a CH2 group or an S atom to obtain a naphthyl ring or sulfur, respectively. Completion of the base ring, and II formation of VI turn 135964.doc -18· 200927740, that is, by formulating the compound in the same manner as described above for the fluorenyl ring, the compound of formula II can be prepared according to the method described above. , III compounds have the same meaning❹

D

The compound of formula III can be prepared according to the method described above, that is, by the compound of formula IV

Conversion of r3 OH IV to a compound of formula III wherein R1, 尺2 and 尺3 have the same meaning as above. In one embodiment, the invention provides a method of preparing a compound of formula B as shown below. i) Η) in)

OH

Iv) a) iv) b) NHC02Me The appropriate reaction conditions for the above steps are 135964.doc •19- 200927740 i) Tri-acetic acid 'hexamethylenetetramine' 8 〇 °c followed by urc, water. : Diterpene Amine, propylene guess... nitrogen bicyclo [2 coffee water, 70 C; iii) a) sodium hydroxide, water, 95t: ; b) concentrated hydrochloric acid; 1V) a) propanil, triethylamine, two stupid Phosphate-based ruthenium compound water two-gas methane 'methanol, 60 ° C, petroleum ether. All of the steps in the process of the invention are safe and economical and result in good products. In one embodiment, a compound of formula B prepared according to any of the methods of the invention can be converted to a compound of formula E.

Ε wherein Ru represents hydrogen, alkyl or alkylaryl; 11 is 1, 2 or 3; and the cores, I and R3 have the same meanings as given above. The compound of formula E can be a compound having the formula P s.,

-NH

P

NH2HCI This conversion can include the following steps. Conversion of a compound of formula B to the S or R enantiomer of a compound of formula A, 135964.doc • 20-200927740

R4 A wherein Ri, 2, & 3 and R4 have the same meanings as given above. In one embodiment, at least one of R1, heart, and 1 is fluorine. Compound A suitably has the formula:

In one embodiment, R4 is (^ to decyl. t is optionally methyl, ethyl or tBu. R4 is preferably fluorenyl. In another embodiment, I is aryl. In an embodiment Wherein compound VIII is in the S enantiomer form. In another embodiment, compound A is in the R enantiomer form. The R or S enantiomer of compound A can be converted to a compound of formula c or The corresponding R or S enantiomer of its salt.

Wherein Rr I and & have the same meaning as given above. The compound of formula c or a salt thereof or an enantiomer of the same may be converted to the corresponding R or S enantiomer of a compound of formula e or a salt thereof;

Wherein Rf, I and R3 have the same meaning as given above 135964.doc • 21 - 200927740 hydrogen, alkyl or alkylaryl; and η is 1, 2 or 3. Preferably, hydrazine is (R)-5-(2-aminoethyl)-1-(6,8-difluoroacridin-3-yldialdehyde. Met-2-oxime. In one embodiment , the R or S enantiomer of the compound of formula C and the compound of formula D2

D2

Reacting with a water-soluble thiocyanate in the presence of an organic acid in a substantially inert solvent. Subsequent removal of the protecting group of intermediates F to I:

S^NH 4ScrNi NR12R13

Thus generating a compound of formula E or its corresponding pair"

S.

E 135964.doc -22- 200927740 wherein Ri, R2 and R3 have the same meaning as given above, η represents i, 2 or 3; Ru represents hydrogen, alkyl or alkylaryl '1^1 represents hydroxy protection Base! ^3 represents an amino protecting group, or Rll is as defined above but together with Is represents an phthalimido. The water-soluble thiocyanate is preferably an alkali metal thiocyanate or a tetraalkylammonium thiocyanate. The solvent is preferably an organic solvent. In the embodiment, 'η is 2 or 3. In another embodiment, at least one of R^, R2 and R3 is fluorine. The compound of formula E is optionally as follows: (S)-5-(2-aminoethyl)-oxime (ΐ,2,3,4-tetrahydronaphthalene-2-yl)d, % dihydroimidazole· 2 - Sulfur brewing||(8)-5-(2-Aminoethyl)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3- Dihydroimidazole-2-thione; (R)-5-(2-Aminoethyl)-1-11 g. -3--3-yl-1,3-dihydromiol or sitting _2_thione; (R)-5-(2-aminoethyl)-1-(6-hydroxyindole. -3-yl) _ι,3-dihydroimidazole-2-thione; (R)-5-(2-aminoethyl)-1-(8-hydroxyacridin-3-yldihydroimidazole-2-thione; R)-5-(2-Aminoethyl)-1-(6-methoxybenzo-3-yl)-1,3-dihydroimidazole-2-thios; (R)-5-( 2·Aminoethyl)-1-(8-decyloxyguanidin-3-yl)_ι,3-dihydroimidazole-2-thione; (R)-5-(2-Aminoethyl) -1-(6-fluoro-bito σ-end-3-yl)_ι,3_diazepine σ sit-2-thione; (R)-5-(2-aminoethyl)-1-(8-乱ρ克°完-3-基)_ι,3_二凰米闻-2 - sulfur 135964.doc -23- 200927740 ketone; (R) -5_(2_aminoethyl)-1·(6, 7 - 二气^^-3·yl)-l,3 -diaza methane ° sitting -2_thione; (R) -5-(2-aminoethyl)-1-(6,8_two Gas ^^-3-yl)-1,3-dichloro-flavor °-thiol; (S) -5_(2_aminoethyl)-1_(6,8-digas^^-3 -Base)_1,3_二虱σ米嗤·2_ Sulfur Sl^, (1^)-5-(2-Aminoethyl)-1-(6,7,8-di-gas bite-end-3 -yl)-1,3-di-milk 13 m. Sit · ❹ 2-thione; (R) - 5 _(2·aminoethyl)-1-(6-gas-8-methoxy ^^-3 -yl)-1,3·diazolidine-2-thione; (R)-5-(2-aminoethyl)_1-(6-oxime!--8-bite σ ·3-yl)-1,3-diazol imidazole-2-thione; (R)_5-(2-aminoethyl)-1-(6-nitromethyl gram-fin-3-yl) · 1,3 · two-flavor 嗤-2_ thiopurine, (R)-5-(2-aminoethyl)-1-(8-nitro ke..-3-yl)-1,3-di Milk σ m嗤·2_ thioketone; (R)-5-(2-aminoethyl)-1-[6-(ethyl arylamino)^^-3-yl]-1,3·di-imidazole -2-thione; (R)-5-aminoindenyl-1 gram σ-end 3-yl-1,3-two wind 17 m 17-sodium-sulfur net, (R)-5-amino group Methyl-1 - (6-yl-based p-gram 11-end-3-yl)_1,3·二风°米° sit-2_ thiopurine, (R)-5-(2-aminoethyl)- 1-(6-radio-7-membered group 1:7 g ° ° _3·yl)-1,3-diazaimidazole-2-thione; (R)-5-aminomethyl-l- (6,8-two gas mouth gram ° complete -3- base) -1,3 · two gas mouth meters ° sit-2-sulfurium; 135964.doc •24· 200927740 (R) -5-(3·aminopropyl Base)-l-(6,8-dione ΐI 克u _3-yl)-l,3-diaza τJ-m fl-sodium-2-thioindole, (S) -5-(3-aminopropyl Base)-l-(5,7-di-gas-1,2,3,4-tetrazane-2 -yl)-1,3·dihydroimidazole-2 -thione; (R,S)-5-(2-aminoethyl)-1-(6-sulfanylsulfonate _3·yl)-1,3-diazosazole-2-sulfur Ketone; (R,S)-5-(2-aminoethyl)-1-(6-methoxythiazol-3-yl)-1,3-dihydroimidazole-2-thione; R)-5-(2-benzylaminoethyl)-1-(6-methoxyindol-3-yl)-1,3-dihydroimidazole-2-thione; (foot)-5 -(2_n-ylaminoethyl)-1-(6-trans-substrate π-end·3·yl)-1,3-diazosazole-2-thione; (R)-l-(6 - bite through the base. -3 -yl)-5-(2-decylaminoethyl)_1,3-di-flavonol-2-thione; (R)·1_(6,8_二气p克。完-3 - Base) 5-(2-mercaptoaminoethyl)·1,3·diodor oxime-2-sulfo or (R)-1-bit. Complete -3 -yl-5 - (2-methylaminoethyl)_1,3_two wind ρ m sal -2- sulfur hole. The hydrazine compound may also be a salt of the following: (S) -5-(2-aminoethyl)-1-(1,2,3,4·tetrachloroqin-2-yl)-1,3 - dinitrogen 11 m 0 sit-2-thione; (S)-5-(2-aminoethyl)-1·(5,7·difluoro-1,2,3,4-tetrazine- 2-(yl)-1,3_dihydroimidazole-2-thione; (R)-5-(2-aminoethyl)-1-^σ·3·yl·1,3 -two wind 嗦° Sodium-2-thioindole; (R)-5-(2.Aminoethyl)-1-(6-|^-based bite-3-yl)_1,3_dichlorofeed. Sitting -2- 135964.doc -25- 200927740 thioketone; (R)-5-(2-aminoethyl)-1-(8-transyl^^-yl)-1,3-dichloro 0 m ° sit-2_thione; (R)-5-(2-aminoethyl)-1-(6-methoxyacridin-3-yl)-1,3-dihydroimidazole-2- (R)-5-(2-Aminoethyl)-1-(8-methoxyindol-3-yl)-1,3-dihydroimidazole-2-thione; (R) -5-(2-Aminoethyl)-1-(6-gasbitate-end-3-yl)-1,3-dinitro-p-tiprop-2-thioindole; (R)-5-( 2-Aminoethyl)-1-(8-oxo-bit.--3-yl)-1,3-diaza-p-m-pyridin-2-thioindole; (R)-5-(2-amino group Ethyl)-1-(6,7-dioxo ρg σ -3--3-yl)-1,3-diaza scent ° sulphur -5⁄4, (R) _5_(2·aminoethyl) -l-(6,8·二风t^:rg π完-3-yl)·l,3-diazo σm σ sit-2-thione; (S) -5-(2-amino group Ethyl)-1_(6,8-di-milk p-g -3 -yl)-1,3-di-flavored _2_thione; (11)-5-(2-aminoethyl)-1 -(6,7,8-trifluoroindol-3-yl)-1,3-dihydroimidazole-medicine 2-thione; (R)-5 - (2-aminoethyl)-1-( 6-Chloro-8-oxime-biting -3-yl)-1,3-diazolidine-2-thione; (R)-5-(2-aminoethyl)-1-(6 -曱oxy-8- Biting ° _3_ base)-1,3-dichloroimidazole-2-thione; (1^)_5-(2-aminoethyl)-1-(6-nitro*7 g °- 3-based)-1,3-dioxin. Sodium-2-thione; (R)-5-(2-aminoethyl)-1 ·(8-nitro blowing. 3-yl)-1,3 - two rat taste ° sitting -2 135964. Doc -26- 200927740 thioketone; (R)-5-(2-aminoethyl)-1-[6-(ethyl arylamino) bite-end-3-yl]-1,3-diazolidine (2-)-thiol-1; Base-1-(6-trans-base bit 11--3-yl)-1,3-dichloro-11 m嗤_2_thione; (R)-5-(2-aminoethyl)-1- (6 - thio--7-based base 11-end-3-yl)-1,3-di-imidazole-2-thione;

(R)-5-aminomercapto-1(6,8_diox^^-3.yl)-1,3-two wind 13 mw-2·thione; (R) -5-( 3-aminopropyl)-1-(6,8-difluorobitate. -3-ylthione; (S) -5-(3-aminopropyl)-1-(5,7·2 -1,2,3,4-tetrahydroqin-2-yl)-1,3. dihydroimidazole-2-thione; (R,S)-5-(2-aminoethyl)-1 -(6•hydroxy thiopurine. End-3·yl)-1,3_dihydromime. Sodium-2 - thiophene, (R,S)-5-(2-aminoethyl)-1-( 6-曱 基 硫 硫 ° °-3-yl)-1,3-di-flavon-2-thione; (R)-5-(2-arylaminoethyl)-1-(6-曱oxy^^-3·yl)·1,3·dichlorop-mazole-2-thione; (&)-5-(2-pyrylaminoethyl)-1-(6- Substrate 17--3-yl)-1,3-diaza 17-mazole-2-thione; (R)-1-(6-trans-bito-3-yl)-5-(2-A Aminoethyl)-1,3-diazosazole-2 stomach thione; 135964.doc -27- 200927740 (R)-l-(6,8-difluoroacridine_3_yl)·5_ (2·Methylaminoethyl) 1% dihydromiprofen-2-thione or (R)-l-acridin-3-yl-5-(2-methylaminoethyldipyridinium dihydrogen Imidazole 2 -thione. The salt is preferably a hydrochloride. According to another aspect of the invention, Shu compound billion

NH2 J ❹ " wherein Ri, R2 and R3 are the same or different and represent hydrogen, halogen, alkyl, alkyloxy, hydroxy, nitro, alkylcarbonylamino, alkylamino or dialkylamino, Wherein the term alkyl radical means a straight or branched chain hydrocarbon chain containing from one to six carbon atoms, optionally substituted with an aryl group, an alkoxy group, a functional group, an alkoxycarbonyl group or a hydroxycarbonyl group; the term aryl means a phenyl or naphthyl group substituted with an alkyloxy group, a dentate or a nitro group; and the term halogen means fluorine, gas, bromine or

iodine. In one embodiment, at least one of R1, heart, and chemistry is fluorine. The compound ❹ 1 suitably has the following formula IA

Compound 1 can be prepared by any suitable method, such as by any of the methods described above. According to another aspect of the invention, a compound of formula II is provided 135964.doc -28- 200927740

Wherein R1, R2 and R3 have the same meaning as given above. Formula π compounds can be prepared according to any of the methods described above. Suitable for local ^

F

According to another aspect of the invention, a compound of formula V is provided

Wherein R, R2 and R3 have the same meanings as given above. The compound of the formula can be prepared according to any of the methods described above. Compound V suitably has the following formula

According to another aspect of the invention, a compound of formula VI is provided

The center of the VI has the same meaning as given above. (d) The compound can be prepared according to any of the methods described above. Compound vm local 135964.doc -29· 200927740

F The invention will now be described in terms of the following non-limiting examples. Example

CO-W

Example 1: 6,8-Difluoro-2H-acridene-3-nitrile-Compound IVA forming compound IIIA re-forming compound IIA

C6H4F20 MW: 130,09 i) TFA.HMTA ii) DMF, DABCO propylene ride

C|〇H5F2NO MW: 193,15 Difluoroacetic acid (11.25 L' 17.28 kg) and 2,4-difluoro stupid " (IVA, 2.25 kg) were charged to a 100 L reactor; the resulting solution was adjusted to 2〇乞. Fill with hexamethylenetetramine (2 7 〇 kg) with good agitation for about 30 minutes;

The reaction temperature reached 40 °C. The reaction mixture was adjusted to 8 Torr. (: and kept at 80 ° C for at least 1.0 hour, then heated to 115 < t. The reaction mixture was maintained at 115 C for 1800 to 20.0 hours, followed by cooling the reaction to 3 Torr. Water (76.5 L) was charged to the reactor in minutes. The reaction was then adjusted to 2 C and maintained at 2 ° C for at least 4.0 hours. The resulting suspension was then filtered and the filter cake was washed with water (18.0 L and 13.5 L). And then drained for at least 30 minutes. Then use two batches of water wet (ΙΠΑ) in the following steps: Water-containing road (ΠΙΑ), acrylonitrile (7.9 kg), dimethylformamide 3.5 135964.doc 200927740 kg) and water (18.5 L) were charged to a 100 L reactor. With good agitation, DABCO (〇.88 kg) was added to give a clear yellow solution. The reaction mixture was then adjusted to 70 C and the reaction mixture was maintained at 70. (3 for 18, 0 to 20.0 hours 'The reaction mixture was then cooled to 201:. Water (18.4 L) was then charged and the reaction mixture was adjusted to 2 ° C and kept at 2. (: 3 hours. The product was washed with aqueous methanol (7.3 L) (5:1, EtOAc, EtOAc) and dried in vacuo. (IIA, 2.90 kg, 43.5%).

Example 2. 6,8-Fluoro-2Η-Ι»克咬稀-3-methylandrostenamine_Compound ΗA forming compound IA

H2S04 AcOH F Ci〇H5F2NO MW: 193,15

F C10H7F2NO2 MW: 211,16 6,8-Difluoro-2H-nonene_3_carbonitrile (IIA, 2 86 kg) and acetic acid (229 〇 L) were charged to a 1 〇〇L reactor. The resulting suspension was adjusted to catch with good agitation, and then sulfuric acid (10.96 kg) was charged in a single portion. The resulting suspension was then adjusted to IGGt and maintained at loot for 6 G minutes. The reaction mixture was then adjusted to 3 (TC and charged with aqueous isopropanol (34 4 L (2.1 water·ΙΡΑ)) over 20 minutes. The reaction mixture was then adjusted to 5 ° C and kept at 5 ° C for at least 2. 〇hour. The product was then filtered and treated with aqueous isopropanol ((4) L (2.1 'water: ιΡΑ)), aqueous 〇5 N isopropanol potassium hydroxide solution and finally aqueous isopropanol (14.3 L (2:1, water) :IpA)) Washing the cakes, then drying the product in vacuum to obtain a microcrystalline solid 6,8_2 defeated bite spray 135964.doc -31 · 200927740

Dilute-3·carbamamine (ΙΑ, 2.91 kg, 93.6%). Example 3, 8-difluoro-2H-decene _3-ylaminocarbamate · Compound (IV) Formation of compound BA

MW: 211,16 ChH9F2N03 MW: 241,19 . Ci〇H7F2N〇2 φ Put 6,8_ difluoroserate bite _3-cartoamine (at 8 kg) and sterol (44.7 L) into 100 In the L reactor. The resulting suspension was adjusted to 5 °C with good transfer, followed by a sub-gas/water mixture (8.25 L '1.1 equivalent) at a temperature below the listening rate. The reaction mixture was then brought to 5. His kneeling was dropped for 3 minutes. The reaction mixture was sampled and analyzed to confirm that the starting material was completely consumed. Then to maintain the internal temperature below 1 〇. The rate of helium was charged with 15 n gas oxidized nano-fluid (9.3 L). The reaction mixture was maintained at < 1 Torr for 3 Torr, then the reaction mixture was adjusted to 25 ° C. The reaction mixture was maintained at 25 ° C for 2 〇. The reaction mixture was then adjusted to the subsequent addition of 1.5 N hydrochloric acid (2 〇.〇 L), and the resulting suspension was maintained at RC for at least 1.0 hour. The product was then filtered and washed with aqueous decyl alcohol (2×11.5 L (1:1, Hz O. MeOH)) and dried in vacuo at 45 ° C to give 6,8-difluoro-2-indole. Ethyl -3-aminoamine decanoate (2.45 kg, 74.5 %). Recrystallization procedure charged with water (9.1 L), 2-propanol (11.4 L) and 6,8-difluoro-2H-nonene-3-ylcarbamic acid methyl ester (2·28 kg) in 100 L In the reactor. With good 135964.doc • 32. 200927740 The resulting suspension was adjusted to 75 < t and held at 75 until complete dissolution was achieved. The reaction mixture was then held at 75 <t for 3 minutes and then the reaction mixture was adjusted to 5 〇t over 6 Torr and held at 5 〇 for 6 〇 minutes. The resulting suspension was then adjusted to 2 < t over 2.0 hours and held at 2 <>> for at least 60 minutes. The product was then filtered and washed with EtOAc (2 EtOAc, EtOAc (EtOAc): EtOAc (EtOAc) Methyl formate (2 〇 3 kg, 88 8 %).

Example 4: 6,8·di-gas-2H-acridene_3-nitrile·Compound IVA to compound ΙΠΑ Formation of compound IIA to 2,4-difluorophenol (1, 〇 part by weight) at 20 ° C The solution in fluoroacetic acid (5 parts by volume) was added to hexamethylenetetramine (1.2 parts by weight, ΐ·ι mole equivalent) in batches over 30 minutes while maintaining the internal temperature < 50 ° C The reaction mixture is then heated to 8 ° C and maintained at this temperature for at least 60 minutes. The reaction mixture was then heated to 115. (: and maintained at this temperature until the reaction was judged complete by HPLC. The reaction mixture was then cooled to 30. 'After 3 minutes, water (34.0 parts by volume) was added to give a yellow suspension. The suspension was then cooled to < And kept at this temperature for at least 4.0 h. Then the suspension was filtered and then washed with water (8 liters volume). The aqueous aldehyde was then absorbed in acrylonitrile (3.46 parts) at 2 °C. In the volume, 'M-diazobicyclo[2.2.2]octane (0.24 parts by weight) was added and the reaction mixture was heated to 701. Monitoring by HPLC until the reaction was complete, followed by concentration of the reaction mixture under reduced pressure. Drying. The resulting slurry was diluted with aqueous methanol (2.4 parts by volume, 17% water) and cooled to < 5 ° C for 2-3 h. 135964.doc -33 · 200927740 The resulting solid was filtered and subsequently The human was sucked from the aqueous methanol (1.0 part by volume, 33% water) to wash the knee. The title compound was then dried under vacuum at 45 C to a constant weight. Example 5 6'8-Fluoro 2 Η·«Ή埽-3_carboxylic acid _ compound Ruthenium forming compound

IVA

To a solution of sodium hydroxide (52 parts by weight, 25 moles equivalent) in water (14.0 parts by volume) at 2 ° C, M•difluoro-2h•bite dilute nitrile (1 part by weight) ), a suspension is obtained. The reaction mixture was then heated to an apparatus and maintained at 95 C until a clear solution was obtained. The reaction mixture was then monitored by HpLc until the reaction was complete. The reaction mixture was then cooled to wc and 36% hydrochloric acid (1.31 parts by volume, 丨57 parts by weight, 3 〇 molar equivalent) was slowly added to obtain a mobile suspension (mobile suspensi〇np was subsequently cooled to <5C and maintained) At <5. (: at least ^h. The title compound is then filtered and subsequently washed with water (2 x 2.0 vol). Then the product is dried at 4 (rc vacuum) to a constant weight. Example 6: 6,8-II Fluorin-2H-pinene methyl 3-methylcarbamate - compound VIA to form compound VA to form compound ba at 15 ° C, add the entire amount of diphenylphosphonium azide (1 part by volume) 1.09 molar equivalent) to 6,8-difluoro-2H-bite dilute-3-carboxylic acid (1.0 part by weight) in propylene (1 〇.〇 volume) and triethylamine (〇71 parts by volume, 丨〇 9 molar equivalents of the solution. The reaction mixture was then monitored by HPLC until the reaction was complete. The reaction mixture was then diluted with cold water (20.0 parts by volume) to allow the intermediate azide to "cool the suspension to < 1 〇 ° C and kept at <丨〇.〇 for 1,0 h. Then the suspension is filtered and then water 5 parts by volume) Washing. The aqueous wet matter is then taken up in di-methane (7.5 parts by volume) and separated from each phase by 135964.doc -34-200927740. The resulting two-gas calcination solution is dried using sulfuric acid. At 60 ° C, the W addition rate is equal to the collection of the museum (4), the dichloromethane azide solution is added to methanol (60 parts by volume). Once added, continue to distill until the top temperature of the distillation tower reaches 60 Then, the system was set to reflux. The reaction was then monitored by HPLC until the reaction was completed. The reaction mixture was then cooled to <15 ° C and concentrated under vacuum to a volume of 2 parts, followed by di-methane ( The crude reaction mixture was diluted with 7.5 parts by volume and heptane (2.5 parts by volume), then dihydromethane was distilled at atmospheric pressure, and the reaction mixture was concentrated to 6.0 parts of volume. After cooling to 25 ° C, petroleum ether was slowly added. (10 0 parts by volume) to crystallize the title compound. After complete addition, the resulting suspension was cooled to < 5 ° C and maintained at 5 ° C for 1.0 h. The title compound was then filtered and then petroleum ether (5.0 parts by volume) Polyester then dried in vacuo at 35 ° C the product of strange given weight is to be understood that the invention may be modified within the scope of the patent application in the scope of the appended claims.

135964.doc •35·

Claims (1)

200927740 X. Patent application scope: 1. A method for preparing a compound of formula B, B V' 0 The method comprises the compound of formula VII Converted to a compound of the formula B, wherein R!, R2 and R3 are the same or different and represent hydrogen, halogen, alkyl, alkyloxy, hydroxy, nitro, alkylcarbonylamino, alkylamino or a dialkylamine group; the rule 4 is an alkyl group or an aryl group; and R5 is ·Ν3 or -NH2 ' wherein: the term alkyl means straight or branched, containing one to six carbon atoms, optionally an aryl group, a hydrocarbon chain substituted with an alkoxy group, a halogen, an alkoxycarbonyl group or a hydroxycarbonyl group; the term aryl means a phenyl or naphthyl group optionally substituted with an alkyloxy group, a dentate or a nitro group; and the term halogen means fluorine, Gas, bromine or iodine. 2. The method of claim 1 wherein at least R3 is fluorine. 3. The method of claim 1 or 2, wherein R4 is c] to c4. The method of claim 1, 2 or 3 wherein R4 is a decyl group, an ethyl group or a tert-butyl group. 5_If the claim item is any - top: ^古 '土 ^. $ A method of any of the items, wherein R4 is a methyl group. 6. The method of claim 1 or 2 wherein I is a node. 7. The method of any of the preceding claims, wherein the compound has a formula 135964.doc 200927740 8. The method of claim 1 wherein compound VII has formula IA IA. 9_ The method of any one of claims 1 to 6, wherein the compound VII has the formula V 1. The method of claim 1, wherein the compound νπ has the formula VA 11. A method of reacting according to any of the preceding claims. Wherein the transformation method comprises recombination 12. The method of 4, wherein the transformation method comprises a Hoffman recombination reaction. 1 3. The method of claim 9 戎丨 夕 、 、, 车, 丄 - method, wherein the conversion method includes Curtius recombination β 14. The method of claim 7, 8, or 12 In the presence of a hypohalous acid-and an alcohol of the formula R4〇H (wherein r4 has the same meaning as defined in any one of claims 1 to 3 to 6), the amine group is recombined to form an amine group 135964 .doc 200927740 Formate group. The method of the present invention wherein R4 is a methyl group and the conversion method comprises a recombination reaction in the presence of sodium and methanol. 15. Times 16. In the case of claim 9, 〇 or 13 , the T/f fly 3 is removed, wherein the recombination reaction comprises dissolving the compound of formula 1 in the alcohol, adding the dentate salt and maintaining the reaction. The temperature of the object is below l〇 °C. Wherein the #acid salt is a sub-gas acid. 17. The method of claim 14, 15 or 16, salt. ❹ 8. The method of any of the items of the sixth aspect of the present invention, wherein the compound of the formula B is purified by recrystallization. The method of claim 18, wherein the recrystallization method is carried out in a water/2-propanol mixture. 20. The method of claim 7, or the method of any one of claim 7, wherein the compound of formula I is produced from a compound of formula Conversion to a compound of formula I wherein R1, heart and !^ have the same meaning as the compound. 21. The method of claim 2, wherein the compound of formula π has the formula F F 22. The method of claim 20 or 21, wherein the method of converting the II to I comprises hydrolyzing in the presence of an acid. The method of claim 22, wherein the acid is a mineral acid and an organic acid. The method of claim 23, wherein the organic hydrazine is acetic acid. 25. The method of claim 23 or 24 wherein the mineral acid is sulfuric acid. 26. The method of claim 21, wherein the compound of formula b has the formula 27. The method of claim 9, llstl3 wherein the conversion method of forming b from ¥ is included in an alcohol having the formula R4〇H (where &amp; has the same meaning as given in any one of claims 3 to 6) Thermal decomposition is carried out in the presence. 28. The method of claim 27, wherein the thermal decomposition method comprises combining the formula v And the method for preparing the compound of the formula B comprises the following steps. The material is dissolved in an organic solvent, and the reaction mixture is heated to the reflux temperature of the organic solvent. 29. The method of claim 28, wherein the organic solvent is di-methane, toluene or ethyl acetate. The method of claim 27, 28 or 29, wherein the alcohol having sR4〇H is the organic solvent. The method of claim 28, 29 or 30, wherein the process of dissolving the compound of the formula v in the organic solvent is carried out at a temperature of 5 (rc to 7 (rc range). 135964.doc 200927740 32. The method of the item 31, wherein the process of dissolving the compound of the formula v in the organic solvent is carried out at a temperature in the range of from 35 ° C to 8 (the range of TC. 33. The method of claim 32, wherein the compound of the formula The process of dissolving in the organic solvent is carried out at a temperature of about 60 ° C. The method of any one of claims 27 to 33, wherein after the reaction is completed, the reaction mixture is cooled, optionally concentrated and added The second solvent is used to crystallize the compound of the formula B. 35. The method of claim 34, wherein the second solvent is an organic solvent selected from the group consisting of petroleum ether, hexahydrogen, or heptane. 36. The method of claim 34 Wherein the first organic solvent is a water-miscible solvent and the second solvent is water. 37. The method of claim 34, 35 or 36, wherein the cooling method is up to 3 Torr. The method of any one of claims 27 to 37, wherein the method of any one of claims 27 to 37, wherein A compound of formula μ law prepared by the compound of formula VI Ο Conversion to a compound of the formula ν wherein Ri, R2 &amp; R3 have the same meaning as in the oxime of the compound. 39. The method of claim 38, wherein the compound of the formula has the formula 135964.doc 200927740 40. The method of claim 38 or 39, wherein the conversion of the ¥1 formation v comprises the use of a sulfhydryl azide former . 41. The method of claim 38, 39 or 40, wherein the conversion of the hydrazine forming the hydrazine is carried out in the presence of a water miscible solvent. 42. The method of claim 41, wherein the water miscible solvent is acetone, acetonitrile, DMF, THF, dioxane or 1,2-dimethoxyethane. The method of any one of claims 38 to 42, wherein the conversion of the oxime to v is carried out in the presence of a base. 44. The method of claim 40, wherein the sulfhydryl azide forming agent is a diphenylphosphonium azide and the conversion is carried out in the presence of a base. 45. The method of claim 43 or 44, wherein the base is triethylamine, tripropylamine or tributylamine. The method of any one of claims 38 to 45, wherein the compound of formula V is precipitated therefrom by adding cold water to the reaction mixture. 47. The method of claim 46, wherein the suspension of the compound of formula v is cooled, filtered, and the wet cake is extracted with a suitable organic solvent. The method of any one of claims 38 to 47, wherein the compound of the formula 1 is a compound of formula II N II is converted to the compound of formula VI wherein R1, R2 and R3 have the same meaning as in compound νι. 49. The method of claim 48, wherein the compound of the formula has the formula 135964.doc -6- 200927740 50. The method of claim 48 or 49, wherein the converting to form a νι group comprises hydrolyzing a nitrile moiety on the compound of formula II. 51. The method of claim 5, wherein the hydrolysis comprises reacting the compound of formula I with a test in the presence of water followed by treatment with an acid. 52. The method of claim 51, wherein the base is sodium hydroxide, lithium hydroxide or cesium hydroxide. 53. The method of claim 51 or 52, wherein the acid is hydrochloric acid, sulfuric acid or phosphoric acid. The method of any one of claims 20 to 26 or 48 to 53, wherein the method of formulating the compound of formula π is a compound of formula III ❿ is converted to the compound of the formula II, wherein I, R2 and R3 have the same meanings as in the compound „. 55. The method of claim 54, wherein the hydrazine compound has the formula ΙΠΑ 56. The method of claim 54 or 55, wherein the conversion of the III to π comprises a cyclization condensation reaction. 135964.doc 200927740 A. The method of claim 54, 55 or 56, wherein the conversion to π is carried out in the presence of acrylonitrile and hydrazine-diazabicyclo[2.2.2] octane. The method of any one of claims 54 to 57 wherein the reaction mixture is heated to a temperature in the range of 5 ° C to 9 CTC. 59. The method of claim 58, wherein the reaction mixture is heated to a temperature in the range of 赃 to 80 C. The method of claim 59, wherein the reaction mixture is heated to a temperature of about thief. The method of any one of items 54 to 60, wherein the reaction is carried out in a solvent. The method of claim 61, wherein the solvent is pure acrylonitrile. 63. The method of claim 61, wherein the solvent is dmf. 64. The method of any one of claims 54 to 63 wherein the compound is produced from a compound of formula IV The same meaning in the middle. 65. The method of claim 64, wherein the compound of the formula has the formula: wherein the IV OHRi, R2 and R3 have a compound in 66. The method of claim 64 or 65, wherein the method of converting the IV to form III comprises 135964.doc 200927740 reacting the compound of formula iv with a formazaming agent. The method of claim 66, wherein the brewing agent is hexamethylenetetramine. 68. The method of claim 66 or 67, wherein the transformation is carried out in the presence of an acid. 69. The method of claim 68, wherein the acid is trifluoroacetic acid. The method of any one of claims 66 to 69, wherein the temperature of the reaction mixture is raised to 6 ° C to 1 Torr after the addition of the oximation agent. (The temperature in the range. 71. The method of claim 70, wherein the temperature of the reaction mixture is raised to a temperature in the range of from 70 ° C to 90 °. 72. The method of claim 71, wherein The temperature of the reaction mixture is raised to a temperature of about 80 ° C. The method of any one of claims 70 to 72, wherein the elevated temperature is maintained for a period of at least 60 minutes. The method of claim 74, wherein the temperature of the hydrazine reaction mixture is further increased to a temperature in the range of from about 90 ° C to about 13 (the range of TC. 75. The method of claim 74, wherein The temperature of the reaction mixture is further increased to a temperature in the range of from about WOt to about 12 (the range of TC. 76. The method of claim 75, wherein the temperature of the reaction mixture is further increased to about 11 5. (: temperature.) The method of claim 71 to the above, wherein the reactant is cooled to a temperature in the range of from about lit to about 45. 78. The method of claim 77, wherein the reactant is cooled to (d). Approximately 135964.doc 200927740 Temperature in the range of 35 ° c. 79 The method of claim 78, wherein the reaction is cooled to a temperature of about 30 ° C. The method of any one of claims 64 to 79, wherein after the reaction is completed, water is added to form a suspension. 8. The method of claim 8 wherein the suspension is filtered and washed with water. 82. The method of claim 64, wherein the compound of formula b has the formula e F NHC02Me and the method of preparing the compound of formula B includes the following steps: The method of claim 64, wherein the compound of formula B has the formula And the method for preparing the compound of the formula B comprises the following steps: 135964.doc •10- 200927740 N The method of any of the preceding claims, wherein the compound of formula b is converted to the s or R enantiomer of the compound of formula A, A wherein R!, R2, R3, R4 have the same meaning as given in any one of claims i to 6. 85. The method of claim 84, wherein compound VIII has the formula: 86. The method of claim 84 or 85, wherein the 1PR* is C丨 to C4 alkyl. 87. The method of claim 86, wherein ~ is enthalpy, ethyl or tBu. 88. The method of claim 87, wherein R4 is methyl. 89. As requested in item 84 or 85, Dan TI is the basis. 90. The method of any one of claims 84 to 89, which is in the form of an enantiomer. 4, wherein the compound A is in the form of a pair of 91. 91. The compound A is in the form of R to 135964.doc 200927740. The method of any one of claims 84 to 91 wherein the method further comprises converting the R or S enantiomer of the compound oxime to the corresponding R or S pair of the compound of formula C or a salt thereof Structure, Wherein Ri, R2 and R3 are the same or different and represent hydrogen, halogen, alkyl, alkyloxy, hydroxy, nitro, alkylcarbonylamino, alkylamino or dialkylamino' wherein: the term alkane The meaning of a straight or branched chain hydrocarbon chain containing one to six carbon atoms, optionally substituted with an aryl group, a methoxy group, a halogen, a oxycarbonyl group or a hydroxycarbonyl group; and the term nuclide means fluorine, gas, and desert Or foundation. 94. The method of claim 92, wherein the compound of formula C or a salt or an enantiomer thereof is converted to the corresponding R or S enantiomer of a compound of formula E or a salt thereof, ❹ wherein Rl2 represents hydrogen, thio or aryl aryl; and !^ is 1, 2 or 3. The method of claim 93, wherein the R or S enantiomer of the compound of formula c is compared to the compound of formula D 135964.doc • 12-200927740 Reacting with a water-soluble thiocyanate in the presence of an organic acid in a substantially inert solvent. Subsequent removal of the protecting group of intermediates F to I: F G nr12r13 ❹ Thereby producing the corresponding R or S enantiomer of the compound of formula E or a salt thereof, Wherein η represents 1, 2 or 3; R] 2 represents hydrogen, alkyl or alkylaryl, . . . KH represents a hydroxy protecting group and Ru represents an amine protecting group, or R ll is as defined above, R12 and R13 together represent a quinone imine group. 95. The method of claim 94 wherein the water soluble thiocyanate is an alkali metal cyanide or a tetraalkylammonium thiocyanate. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Base ethyl)-1 _ bite-3-yl_ 1,3_di-argon ρ-methane-2-sulfur mesh; ()(2~aminoethyl)-1-(6_base-bite &lt;»End_3•yl)-1,3-dihydroimidazole-2·thione; (R)-5-(2-aminoethyldipyridyl-“-hydroxyindole_3_yl)_i,3 - dihydromilyl sitting 2-sulfo _; (foot) _5_(2_aminoethyl)_ι_(6-methoxyacridine_3·yl)-1,3-dihydroimidazole·2-thione; (11) _5_(2_Aminoethylbub) methoxyindol-3-yl)_ι,3·dihydroimidazole_2·thione; (R)_5彳2_aminoethyl) 1-(6-fluoroacridin-3-yl)-i,3-dihydroimidazole-2-thione; (R)_5_(2·aminoethyl)-1-(8-fluoroindole-3 -yl)-1,3-di-argonimide-2-thione; (R)-5-(2-aminoethyl)-1-(6,7-difluoroindol-3-yl)-i , 3-dihydroimidazole-2-thione; (R)-5-(2-aminoethyl)-1-(6,8-difluoroindole-3-yl)-1,3-dihydrogen Imidazole 2- 2-sulfo-, (S)-5-(2-aminoethyl)-1_(6,8-difluoro-u-pent-3-yl)-1,3_ Imidazole-2-thione; (R)-5-(2-aminoethyl)-1-(6,7,8-trifluoroindol-3-yl)-1,3-dihydroimidazole-2 -thione; (R)-5-(2-aminoethyl)·1-(6-gas-8-methoxyindol-3-yl)-1,3-dihydroimidazole-2-sulfur Ketone; (R)-5-(2-aminoethyl)-1-(6-methoxy-8-gasbiti-3-yl)-1,3-dihydromethane (R)_5-(2-Aminoethyl)-1-(6-nitrobite-end-3-yl)-1,3-dihydroimidazole-2-thione; (R)-5 -(2-Aminoethyl)-1-(8-nitroacridin-3-yl)-1,3-dihydroimidazole-2-thione; (R)-5-(2-Amino B Base)-1-[6-(ethinylamino)phosphonium 11 -3-yl]-1,3·dihydroimidazole-2-thione; (R)-5-aminoindenyl ketone- 3-yl-1,3-dihydro-sodium-2-thione; (R)-5-aminoindolyl-1_(6-radio-p-butyl)-1,3-dihydropropanoid- 2-thioindole, (R)-5-(2-aminoethyl)-1-(6-trans-yl-7-nodal bite-end-3-yl), 1,3 -- odor ° sitting- 2- 135964.doc -14- 200927740 degree 嗣, (R) '5' aminomethyl-1-(6,8-difluorocarbazone-3-yl)-l,3-diodoric claw class' r)_5_(3_Aminopropyl)·ι_(6,8_Difluorotrkντ完·3_基卜H-flavored salium (R) 5 (2-benzylaminoethyl) "·(5) fluorenyl fluorenyl)-indole, 3-dihydroimidazole-2-thione; (R)-5-(2-benzyl face .·············· Ethyl)-1,3-dihydromethane 0 sitting _ 2 melon ketone, fluoroacridine _3_yl)_5_(2_methylaminoethyl), ❹ I'3 monohydroimidazole-2 thiol Or (R)-l-indol-3-yl-5-(2-methylaminoethyl)-1,3-dihydroimidazole-2-thione. The method of any one of claims 94 to 96, wherein the compound of the formula E is a salt of the compound: (R)_5-(2'aminoethyl)_1_咣咣_3_yl_1,3 -monochloromethane-2-thione; (R)-5-(2-aminoethyl)-1-(6-carbyl t--3-yl) 1'3-monohydroimidazole_2 Sulfur _; Aminoethyl)-indole-(8.hydroxyl το 3-yl^^, hongdihydroimidazole_2•thione; (R)_5_(2_Aminoethylbub (6·曱Oxygen) Base 吱 _3_ base)]} two odor spit _2 thioketone; (8) _5_(2_Aminomethyl)-1-(8-methoxyacridine-3-yl) 丨, 3_ Dihydroimidazole-2-thione; (R)-5-(2-Aminoethyl)_i_(6-fluoroacridine_3 hydrazin, % dihydroimidazole _2 thiol; (R)- 5-(2-Aminoethyl)-7 (8-fluoroindole-3-yl, w,% dihydroimidazole-2-thione; (R)_5-(2-Aminoethylbub^^difluoro咣咣_3_yl)_ I,3-dihydroimidazole-2-thione; (R)_5_(2-aminoethyl)difluoroanthracepin-3-yl)-1,3-dihydrogen Imidazole-2-thione; (8) _5_(2-aminoethyl)_1_(6,8-difluoroindol-3-yl)-1,3-dihydroimidazole-2-thione; (11 )_5_(2_Aminoethyl)-1-(6,7,8-difluoro'1g _3_yl)_1,3_dihydroimidon-2-ylthione (R)-5-(2-Aminoethyl)-1-(6-gas oxime oxime_3_yldihydrogen 135964.doc * 15 - 200927740 imidazole-2-thione; (R)- 5-(2-Aminoethyl)-b (6-methoxy-8-azetidin-3-yl)-1,3-dihydromiso-2-thione; (R)-5- (2-Aminoethyl)-1-(6-stone-succinyl-3-yl)-1,3-dihydroimidazole-2-thione; (R)-5-(2-Aminoethyl) - 1- 0 nitroindol-3-yl)-1,3-dihydroimidazole-2-thione; (R)-5-(2-aminoethyl)-1_[6-(ethenyl) Amino) acridine-3-yl]-1,3·dihydroimidazole-2- «thione; (R)-5-aminomethyl-1-acridin-3-yl-1,3-di Hydrogen imidazole-2-thiol ketone; (R)-5-aminomethyl-1-(6-hydroxyindol-3-yl)-1,3-dihydroimidazole-2-disulfide _; (R) _5-(2-Aminoethyl)-1-(6-hydroxy-7-benzyl acridine-3-yl)-1,3-dihydroimidazole·2·thione; (R)-5-amine Methyl-1-(6,8-difluorop-butyl-3-yl)-1,3-dihydroimidazole-2-thione; (R)-5-(3-aminopropyl)- 1-(6,8--fluorop-butyl-3-yl)-1,3-dihydroflavor&lt;» sit-2-thione; (R)-5-(2-pyrylaminoethyl )-1-(6-methoxyacridin-3-yl)-1,3-di-n-imidazole-2-thione; (R)- 5-(2·benzylaminoethyl)·1-(6-hydroxyindole “end-3-yl)-1,3-dihydroflavin-2-thione; (R)-l-(6 -hydroxyindole-3-yl)-5-(2-methylaminoethyl)-1,3-dihydroimidazole-2-thioindole; (R)_i_(6,8-difluoroanthracene- 3-yl)-φ 5_(2_methylaminoethyl)·1,3-dihydroimidon-2-thione or (R)-lp gram spray 3- 3--5-(2-A Aminoethyl)-1,3-dihydroimidon-2-inone. 99. The method of claim 98, wherein the salt is a hydrochloride salt. The method of any one of claims 94 to 95, wherein the compound of formula e is the R or S enantiomer of the compound of formula P. 135964.doc -16- 200927740 101. - a compound of formula I, Wherein Ri, R2 and R3 are the same or different and represent hydrogen, halogen, alkyl, • alkyloxy, hydroxy, nitro, alkylcarbonylamino, alkylamino or dialkylamino, wherein: The term alkyl means a straight or branched chain hydrocarbon chain containing from one to six carbon atoms, optionally substituted by aryl, alkoxy, dentate, alkoxycarbonyl φ or hydroxycarbonyl; the term aryl means optionally A phenyl or naphthyl group substituted by an alkyloxy group, a halogen or a nitro group; and the term i means means fluorine, gas, bromine or iodine. 102. The compound I of claim 101, which has the formula IA 103.—Formula V compound ❹ fV, 〇' V 104. The compound V of claim 103, having the formula VA 135964.doc -17- 200927740 106. The compound VI of claim 105, having the formula VIA 107. - Compound of formula II 108. The compound II of claim 107, which has the formula IIA The compound according to any one of claims 101, 103, 105 or 107, wherein at least one of R!, R2 and R&gt;3 is fluorine. 135964.doc 18- 200927740 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best display invention. Characteristic chemical formula: N 0, 0 Y r4 B 135964.doc -6-